Does Giving Very Premature Babies Less Fat Through a Drip Help Protect Them from Jaundice Harm?

What a Houston study by Holzapfel and colleagues (J Pediatr 2026) found when it compared two doses of intravenous fat in babies born extremely early

Babies born very early usually receive fat through a drip because their bodies need energy before they can feed fully by mouth. Doctors have wondered whether a higher dose of this fat might let more of the yellow jaundice pigment reach the brain. A study of 134 very premature babies in Houston found that a lower dose did not change a hearing-pathway test, although worrying levels of "free" jaundice pigment showed up more often with the usual higher dose.

Why fat in the drip and jaundice are connected

Most babies look a little yellow in their first days. The colour comes from bilirubin, a substance made when old red blood cells are broken down. In the blood, most bilirubin rides on a carrier protein called albumin, much as passengers sit safely inside a bus. A small amount is "unbound", meaning it travels on its own, and it is this free portion that can slip into the brain. The parts of the brain that handle hearing are especially sensitive.

Babies born very early, before about 27 weeks of pregnancy, cannot digest enough milk at first, so they are fed through a drip. This intravenous nutrition includes a fat emulsion, a milky liquid made here from soybean oil and known by the brand name Intralipid. Fat is a vital source of energy, and the drip is also how these babies get "essential" fats, which the body cannot make for itself; without them, a deficiency can develop [1][2]. When the fat is broken down, though, it releases free fatty acids, and these can compete with bilirubin for seats on the albumin "bus", pushing more bilirubin out on its own.

A worry that goes back many decades

The researchers who ran the new study describe this concern as one that doctors have raised "for 50 years" [1]. Its history is older still. In the 1950s, a study comparing two antibiotic treatments in premature babies found different rates of death and of kernicterus, the serious brain damage that bilirubin can cause [3]. One of those medicines turned out to push bilirubin off albumin, a lesson that still shapes how doctors think about drugs and other substances that do the same [1]. By 1976, doctors were already writing about how to use Intralipid sensibly in newborns [4].

Later studies measured the free bilirubin directly. One found that fat through the drip raised free fatty acids and free bilirubin in babies born at 28 weeks or earlier, but not in older babies [5]. Another, in 97 premature babies, found that free bilirubin rose step by step as the fat dose went up from 0 to 3 grams per kilogram of body weight per day, and that the usual jaundice light treatment lowered the standard blood test but not the free bilirubin in the youngest babies [6]. Experts asked in print whether this was "a cause for concern" [7]. Laboratory tests have since shown that fatty acids from Intralipid can push bilirubin off albumin about as strongly as that old 1950s medicine [8].

There was a further problem. The routine jaundice test measures total bilirubin, both the carried and the free kind together. In premature babies the free portion can be high even when the total looks fine [9], and premature babies carry more free bilirubin for the same total than babies born at term [10]. In a large study of over 1,100 very small babies, those with the highest free bilirubin levels were more likely to have serious developmental problems later, and the authors warned that the routine test can give "a false sense of security" [11]. Meanwhile, the fat product's instructions recommend building up to 3 grams per kilogram per day [1], and expert nutrition guidelines admit that the evidence behind most of their advice on drip feeding for premature babies is weak [12].

How the hearing pathway acts as an early warning sign

To find out whether fat dose matters, the researchers needed a way to look for early signs of bilirubin harm. Bilirubin damage often starts in the brainstem, the part of the brain that relays sounds from the ear [13]. A painless test called the brainstem auditory evoked response (BAER) plays clicks through small earphones while sticky pads on the head record the brain's electrical reply. Doctors look at how long the signal takes to reach a peak called "wave V". A longer delay can be a sign of bilirubin injury, and doctors have described a baby whose test improved once bilirubin was brought down [14]. A similar test also helps doctors recognise bilirubin brain injury in older newborns with severe jaundice [15].

What the researchers did

The study took place in one large neonatal intensive care unit (NICU) at Children's Memorial Hermann Hospital in Houston, Texas, between 2021 and 2024 [1]. It included 134 babies born before 27 weeks of pregnancy or weighing 750 grams or less. With their parents' consent, babies were assigned by chance, like a coin toss, to one of two fat plans for their first 14 days. Half had their daily fat capped at 1.5 grams per kilogram, enough to prevent a shortage of essential fats; half followed the usual plan, with a cap of 3 grams per kilogram. In both groups, nurses and doctors checked blood fat levels every day and paused increases if the levels rose too high.

All the babies were also part of a study run by the US national research network of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, which compared two ways of giving jaundice light treatment: continuously, or switched on and off in cycles. This let the researchers check whether the type of light treatment changed the effect of the fat dose. The Houston team had earlier tested cycled light treatment in 305 small babies at six US hospitals [16]. Hearing tests were planned from about 36 weeks after the start of pregnancy, and on average were done at 38 to 39 weeks; an expert who did not know which group each baby was in read the results.

What they found

The first surprise was how much fat babies really received. Because doses were often paused when blood fat levels rose, the usual-dose group averaged about 2 grams per kilogram per day rather than 3, and the lower-dose group about 1.1 [1].

The main result was that the hearing test looked much the same in both groups. Among the 110 babies included in the main comparison, the wave V signal arrived after an average of 7.36 thousandths of a second in the lower-dose group and 7.22 in the usual-dose group; the two groups did not clearly differ. The type of light treatment did not change this. One baby in each group had a missing wave V that the researchers linked to bilirubin.

The free bilirubin results were less reassuring. Average levels were similar, but high readings (40 or more on the scale used) appeared in 4 of the lower-dose babies (about 6 in 100) and 9 of the usual-dose babies (about 16 in 100). Some of these high readings happened when the routine total bilirubin test looked low. Those high readings did not come with a worse hearing test, and the researchers could not be certain the difference between groups was not down to chance.

Survival and other complications were broadly similar. Ten babies in the lower-dose group and seven in the usual-dose group died before going home, and growth was alike in both groups.

What this means for families

If your baby is receiving fat through a drip, this study offers some reassurance: at the doses this hospital actually gave, the usual plan did not delay the hearing-pathway signal. Fat remains an important part of early nutrition. The study also shows why your care team watches blood fat levels closely and adjusts the drip; that careful monitoring is likely part of why doses stayed moderate here.

The authors are careful not to overstate their results. The study was fairly small and took place in one hospital, and other units may give more fat. They believe that hospitals giving higher doses could see higher free bilirubin and more risk [1]. Bilirubin injury, when it happens, can cause lasting hearing problems [13] and difficult movement problems [17], so the question is worth answering well. If you have questions about your baby's nutrition, jaundice or hearing checks, your neonatal team is the best place to start. You may also find In[Neo]Sight's article on hearing loss in NICU babies helpful.

What researchers are working on next

The babies in this study are being followed until about two years of age to see how they develop, and those results are not yet available [1]. The researchers are calling for a much larger study across many hospitals to confirm whether usual fat doses are safe for the smallest babies. Other work is looking at fat emulsions made from a mix of oils, which expert guidelines have linked to less severe eye disease of prematurity than soybean oil alone [12].

The take-home message

In one Houston hospital, giving very premature babies half the usual maximum amount of fat through the drip did not change a sensitive hearing-pathway test. Higher free bilirubin readings were more common with the usual dose, sometimes hidden behind a normal-looking routine test. For now, careful monitoring of fat levels remains the practical safeguard while larger studies seek a firmer answer.

References

  1. Holzapfel LF, Tyson JE, Shapiro SM, et al. Parenteral Lipid Dose and Bilirubin Neurotoxicity in Extremely Preterm Infants: A Factorial Randomized Trial. J Pediatr. 2026;297:115225. doi:10.1016/j.jpeds.2026.115225 ↩
  2. Gramlich L, Ireton-Jones C, Miles JM, Morrison M, Pontes-Arruda A. Essential Fatty Acid Requirements and Intravenous Lipid Emulsions. JPEN J Parenter Enteral Nutr. 2019;43(6):697-707. doi:10.1002/jpen.1537 ↩
  3. Silverman WA, Andersen DH, Blanc WA, Crozier DN. A DIFFERENCE IN MORTALITY RATE AND INCIDENCE OF KERNICTERUS AMONG PREMATURE INFANTS ALLOTTED TO TWO PROPHYLACTIC ANTIBACTERIAL REGIMENS. Pediatrics. 1956;18(4):614-625. doi:10.1542/peds.18.4.614 ↩
  4. Bryan H, Shennan A, Griffin E, Angel A. Intralipid–Its rational use in parenteral nutrition of the newborn. Pediatrics. 1976;58(6):787-790. doi:10.1542/peds.58.6.787 ↩
  5. Amin SB. Effect of free fatty acids on bilirubin-albumin binding affinity and unbound bilirubin in premature infants. JPEN J Parenter Enteral Nutr. 2010;34(4):414-420. doi:10.1177/0148607110362529 ↩
  6. Hegyi T, Kleinfeld A, Huber A, et al. Effects of Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants. J Pediatr. 2017;184:45-50.e1. doi:10.1016/j.jpeds.2016.12.026 ↩
  7. Amin SB, Maisels MJ, Watchko JF. Early Lipid Infusions and Unbound Bilirubin in Preterm Neonates: A Cause for Concern?. J Pediatr. 2017;184:6-7. doi:10.1016/j.jpeds.2017.01.065 ↩
  8. Hegyi T, Huber A, Oh W, Kleinfeld A. Unbound free fatty acids from intralipid displace bilirubin from albumin, comparable to sulfisoxazole. Pediatr Res. 2026;99(6):2296-2298. doi:10.1038/s41390-025-04673-y ↩
  9. Hegyi T, Kleinfeld A, Huber A, et al. Unbound bilirubin measurements by a novel probe in preterm infants. J Matern Fetal Neonatal Med. 2019;32(16):2721-2726. doi:10.1080/14767058.2018.1448380 ↩
  10. Hegyi T, Chefitz D, Weller A, et al. Factors Affecting the Relationship Between Total and Unbound Bilirubin in Preterm and Term Infants. Acta Paediatr. 2025;114(8):1977-1981. doi:10.1111/apa.70067 ↩
  11. Arnold CC, Maric I, Wong RJ, Tyson JE, Stevenson DK. Unbound bilirubin and risk of severe neurodevelopmental impairment in extremely low birthweight newborns. Pediatr Res. 2025;98(3):1066-1074. doi:10.1038/s41390-025-03872-x ↩
  12. Robinson DT, Calkins KL, Chen Y, et al. Guidelines for parenteral nutrition in preterm infants: The American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr. 2023;47(7):830-858. doi:10.1002/jpen.2550 ↩
  13. Shapiro SM, Popelka GR. Auditory impairment in infants at risk for bilirubin-induced neurologic dysfunction. Semin Perinatol. 2011;35(3):162-170. doi:10.1053/j.semperi.2011.02.011 ↩
  14. Wennberg RP, Ahlfors CE, Bickers R, McMurtry CA, Shetter JL. Abnormal auditory brainstem response in a newborn infant with hyperbilirubinemia: improvement with exchange transfusion. J Pediatr. 1982;100(4):624-626. doi:10.1016/S0022-3476(82)80771-380771-3) ↩
  15. Gelineau-Morel R, Usman F, Shehu S, et al. Predictive and diagnostic measures for kernicterus spectrum disorder: a prospective cohort study. Pediatr Res. 2024;95(1):285-292. doi:10.1038/s41390-023-02810-z ↩
  16. Arnold C, Tyson JE, Pedroza C, et al. Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants: A Randomized Clinical Trial. JAMA Pediatr. 2020;174(7):649-656. doi:10.1001/jamapediatrics.2020.0559 ↩
  17. Shapiro SM, Riordan SM. Review of bilirubin neurotoxicity II: preventing and treating acute bilirubin encephalopathy and kernicterus spectrum disorders. Pediatr Res. 2020;87(2):332-337. doi:10.1038/s41390-019-0603-5 ↩